O-anisamide derivatives

ABSTRACT

O-anisamide compounds and their addition salts effective for the prevention and/or therapy of metabolic diseases such as hyperlipidemia and diabetes, in which peroxisome proliferator-activated receptor (PPAR) being intranuclear receptor, in particular, human PPAR participates, as agonistic drugs thereon, and processes for preparing them, wherein the o-anisamide compounds are represented by a general formula (1)                    
     [wherein R denotes a carboxyl group, carboxymethyl group or CH 2 CHXCOY (here X denotes a mercapto group or S(O)nMe (n=0, 1 or 2) and Y denotes an amino group or hydroxyl group)], their medicinally acceptable salts, and their hydrates.

This application is a 371 of PCT/JP00/05950, filed Sep. 1, 2000.

TECHNICAL FIELD

The present invention relates to o-anisamide derivatives effective forthe prevention and/or therapy of metabolic diseases such ashyperlipidemia and diabetes, in which peroxisome proliferator-activatedreceptor (PPAR) being intranuclear receptor, in particular, human PPARparticipates, as agonistic drugs thereon, their addition salts,processes for preparing them, and medicinal compositions containingthese compounds.

BACKGROUND TECHNOLOGIES

The peroxisome proliferator-activated receptor (PPAR) is aligand-dependent transcription factor that belongs to intranuclearreceptor superfamily similarly to steroid receptor, retinoid receptor,thyroid receptor, etc., and three isoforms (α type, β(or δ) type and γtype) with different histological distribution have been identifiedhitherto in human and various animal species (Proc. Natl. Acad. Sci.,1992, 89, 4653). There among, the PPARα is distributed in the liver,kidney, etc. with high catabolic capacity for fatty acids and,particularly in the liver, high expression is recognized (Endocrinology,1995, 137, 354), positively or negatively controlling the expressions ofgenes relevant to the metabolism and the intracellular transport offatty acids (e.g. acyl CoA synthetic enzyme, fatty acid-binding proteinand lipoprotein lipase) and apolipoprotein (AI, AII, CIII) genesrelevant to the metabolisms of cholesterol and triglyceride. Moreover,the PPARγ is highly expressed in the fat cells and takes part in thedifferentiation of fat cells (J. Lipid Res., 1996, 37, 907), and so on.In such way, each isoform of PPAR is fulfilling a specific function inthe particular organs and tissues.

Additionally, it is reported that a knock-out mouse of PPARα exhibitshyper triglyceridemia with ageing and becomes obesity mainly byincreased white adipocytes (J. Biol. Chem., 1998, 273, 29577), hence therelevance between activation of PPARa and lowering action of lipids(cholesterol and triglyceride) in blood is suggested strongly.Similarly, it is ascertained that the major intracellular targetproteins of Troglitazone, Pioglitazone and Rosiglitazone beingthiazolidine-2,4-dione derivatives that exhibit blood glucose-loweringaction and improving action on hyperinsulinemia are PPARγs, and theyincrease the transcriptional activity of PPARγ (Endocrinology, 1996,137, 4189, Cell., 1995, 83, 803 and 813). Hence, the relevance betweenactivation of PPARγ and glucose-lowering action is suggested strongly.

When considering such functions of transcriptional factor called PPAR,for a compound that activates human PPAR, medicinal use aiming at thelowering action of lipids (cholesterol and triglyceride) in blood and/orthe blood glucose-lowering action can be expected.

For compounds having an affinity to PPARα as ligands of PPARα,eicosanoides, in particular, 8-hydroxyeicosatetraenoic acid (8-HETE) and8-hydroxyeicosapentaenoic acid (8-HEPE) are reported (Proc. Natl. Acad.Sci., 1997, 94, 312).

However, these endogenous unsaturated fatty acid derivatives areunstable and difficult to be offered as medicinal drugs, and, at thesame time, they have different structure from the inventive compounds.Moreover, compounds having agonistic action on PPARα are reported inWO-97/25042, WO-97/36579, etc., but all of these have differentstructure from the inventive compounds and, at the same time, the effectof agonistic action is also never satisfied in strength. For compoundshaving agonistic action on PPARγ, a series of thiazolidine-2,4-dionederivatives are known in Japanese Unexamined Patent Publication Nos. Sho60-51189, Sho 61-267580, Hei 1-131169, etc. However, all have differentstructure from the inventive compounds.

It is pointed out that the hyperlipidemia and the diabetes are principaldiseases that modern times have to tackle and, at the same time, thesebecome risk factors and link up with the atherosclerotic diseases, inparticular, coronary atherosclerotic disease. Hence, from a viewpoint ofthe therapy or prevention thereof, the development of a therapeutic drugfor metabolic diseases being effective and having high safety based onnew action is desired strongly.

DISCLOSURE OF THE INVENTION

As a result of diligent studies paying an attention to the specificroles on the lipometabolism, adipocyte differentiation, of human PPAR,and aiming at the creation of structurally novel drug with higheffectiveness and safety as a therapeutic drug for metabolic diseases,the inventors have found that o-anisamide derivatives represented by afollowing general formula (1) have excellent agonistic action on humanPPAR and are useful as therapeutic drugs for metabolic diseases, leadingto the completion of the invention.

Namely, the invention relates to o-anisamide derivatives represented bya general formula (1)

[wherein R denotes a carboxyl group, carboxymethyl group or CH₂CHXCOY(here X denotes a mercapto group or S(O)nMe (n=0, 1 or 2) and Y denotesan amino group or hydroxyl group)], their medicinally acceptable saltsand their hydrates.

The medicinally acceptable salts of the compounds represented by thegeneral formula (1) in the invention are of common use and metal salts,for example, alkali metal salts (sodium salt, potassium salt, etc.),alkaline earth metal salts (calcium salt, magnesium salt, etc.) andaluminum salt are mentioned.

Moreover, the compounds, R being CH₂CHXCOY, in the general formula (1)of the invention include optically active substances based on asymmetriccarbon, and further, in the case of X being SOMe group, they includestereoisomers based on their three dimensions, but all of these isomersand mixtures are to be included in the scope of the invention.

According to the invention, compounds (1), being said general formula(1), can be prepared through processes shown in following diagram.

Namely, compounds represented by a general formula (1-a) can be preparedby condensation, leaving carboxyl group as it is or after converted itto reactive derivative according to usual method in the process shown inthe diagram above.

In the case of conducting the reaction by leaving carboxylic acid as itis, the reaction can be performed in an inert solvent such as methylenechloride, chloroform, dioxane or N,N-dimethylformamide in the presenceof condensing agent in the presence or absence of base, and further inthe presence or absence of additive. As the condensing agent, forexample,dicyclohexylcarbodiimide,l-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, diethyl cyanophosphonate, diphenylphosphoryl azide,carbonyldiimidazole or the like can be mentioned. As the base, forexample, alkali metal hydroxide such as sodium hydroxide, alkali metalcarbonate such as potassium carbonate, or organic base such as pyridineor triethylamine can be mentioned. As the additive,N-hydroxybenzotriazole, N-hydroxysuccinimide,3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine or the like can bementioned.

In the case of using reactive derivative, the reaction can be performedin an inert solvent such as methylene chloride, chloroform, dioxane orN,N-dimethylformamide in the presence or absence of, for example, alkalimetal hydroxide such as sodium hydroxide, alkali metal carbonate such aspotassium carbonate, or organic base such as pyridine or triethylamineas a base. As the reactive derivative, acid chloride, acid bromide, acidanhydride, carbonylimidazole or the like can be mentioned. The reactioncan be performed at a reaction temperature of −20° C. to 100° C.,preferably 0° C. to room temperature.

Compounds represented by a general formula (1-b) can be prepared byoxidation using usual oxidizing agent, followed by, if need be,hydrolysis. Namely, in the case of R1 being formyl group, the reactioncan be performed using usual oxidizing agent, for example, chromiumoxide, potassium permanganate, silver oxide or peroxide, but theoxidation using Jones reagent that uses chromic acid is preferable. Thereaction temperature is preferable to be under cooling with ice to roomtemperature. In the case of R1 being cyanomethyl group, the reaction canbe performed using peroxide, acid and base, but it is preferable to useacid such as concentrated sulfuric acid or concentrated hydrochloricacid, hydrogen peroxide or the like to convert to carbamoylmethyl group,followed by hydrolysis using base such as sodium hydroxide or potassiumhydroxide. The reaction can be performed at a reaction temperature of50° C. to refluxing temperature of solvent in a reaction solvent ofalcohol-water system (methanol, ethanol or the like).

Compound, X₂ being methylthio group in a general formula (1-d), andcompounds represented by a general formula (1-e) can be prepared byconverting compound, R1 being nitro group among the compoundsrepresented by the general formula (1-a), to reduced amino form (1-c) inan organic solvent such as ethanol, ethyl acetate orN,N-dimethylformamide at room temperature to under heating at ambientpressure to 329 kPa in the presence of catalyst such as palladium oncarbon, followed by Meerwein arylation reaction, and further by reactingwith NaSMe. Namely, the Meerwein arylation reaction can be conducted bydiazotizing the amino form obtained by reduction with nitrite such assodium nitrite in an organic solvent, for example, alcohol such asmethanol or ethanol, ketone such as acetone or methyl ethyl ketone,water or mixture of these in the presence of hydrogen halide such ashydrochloric acid or hydrobromic acid, and then by reacting catalyticquantity of cuprous salt such as cuprous oxide or cuprous chloride inthe presence of acrylamide or acrylic ester (methyl, ethyl, benzyl esteror the like). Further, the methylthio conversion can be performed byheating to by refluxing in an organic solvent, for example, alcoholsolvent such as methanol or ethanol in the presence of NaSMe. Moreover,(1-e) being ester form can be derived to corresponding carboxylic acidform by hydrolyzing under a temperature condition of room temperature torefluxing in the presence of base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide or acid such as hydrochloric acid orsulfuric acid. Moreover, in the case of X₂ being acetylthio group in thegeneral formula (1-d), this can be prepared by conducting Meerweinarylation reaction of amino form (1-c), and then by reacting withpotassium thioacetate. The reaction can be performed at room temperatureto 50° C. in an organic solvent, for example, tetrahydrofuran, dioxaneor the like.

Compounds, X₃ being methylsulfinyl or methylsulfonyl in a generalformula (1-f), and compounds represented by a general formula (1-g) canbe prepared by oxidizing corresponding compound, X₂ being methylthiogroup in the general formula (1-d), and compounds represented by thegeneral formula (1-e) using peroxide, respectively, and, if need be, byhydrolyzing. As the peroxide, aqueous hydrogen peroxide, perbenzoicacid, peracetic acid, m-chloroperbenzoic acid (mCPBA) or the like can bementioned. The reaction can be performed under cooling with ice to atroom temperature in an organic solvent, for example, methylene chloride,chloroform, ethyl acetate or the like. Moreover, the sulfonyl form (n=2)can be obtained directly using excess peroxide, but it can also beobtained by further oxidizing sulfinyl form (n=1) similarly afterobtaining this. Moreover, the ester form can be derived to correspondingcarboxylic acid form (1-g) by hydrolyzing under a temperature conditionof room temperature to refluxing in the presence of base such as lithiumhydroxide, sodium hydroxide or potassium hydroxide or acid such ashydrochloric acid or sulfuric acid. Similarly, in the case of X₃ beingmercapto group in the general formula (1-f), it is possible to derive tocorresponding mercapto form by hydrolyzing corresponding compound, X₂being acetylthio group in the general formula (1-d), under a temperaturecondition of cooling with ice to room temperature in the presence ofbase such as lithium hydroxide, sodium hydroxide, potassium hydroxide orammonia or acid such as hydrochloric acid or sulfuric acid.

Furthermore, the stereoisomer that can be seen in the sulfinyl form(1-f, n=1) can also be obtained by asymmetric oxidation, for example, bystereoselective oxidation using an optically active ligand such as Davisreagent (J. Am. Chem. Soc., 1992, 114, 1428) or a salen complex.

As the administering form of the inventive compounds, oraladministration such as with tablet, capsule, granule, powder, inhalant,syrup or the like, or parenteral administration such as with injection,suppository or the like can be mentioned.

Best embodiment to put the invention into practice In following, theinvention will be illustrated based on concrete examples, but theinvention is not confined to these examples.

EXAMPLE 1 4-Methoxy-3-[N-(4-trifluoromethylbenzyl)carbamoyl]benzoic acid

To a suspension of 1.00 g of 5-formyl-2-methoxybenzoic acid in 50 ml ofmethylene chloride were added 1.00 ml of triethylamine and 0.60 ml ofethyl chlorocarbonate, and the mixture was stirred for 15 minutes atroom temperature. Then, a solution of 1.17 g of4-trifluoromethylbenzylamine in 10 ml of methylene chloride was addedand the mixture was stirred further for 3 hours at room temperature.After washed with water, the reaction mixture was dried over anhydroussodium sulfate and the solvent was distilled off under reduced pressure.The residue obtained was purified by means of column chromatography(silica gel, hexane:ethyl acetate=1:1) and then recrystallized from amixed solvent of diethyl ether-ethyl acetate-hexane to obtain 1.46 g of5-formyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as colorlesscrystals.

Melting point 116-117° C. Elemental analysis (%) C₁₇H₁₄F₃NO₃ Calcd.(%)C, 60.54; H, 4.18; N, 4.15 Found (%) C, 60.80; H, 4.09; N, 4.28

To 500 mg of 5-formyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamidewere added 20 ml of acetone and 0.5 ml of Jones reagent under coolingwith ice, and the mixture was stirred for 25 minutes. Then, 0.2 ml ofJones reagent were added further and the mixture was stirred for 35minutes. To the reaction mixture were added 100 ml of water, which wasextracted (100 ml×2) with methylene chloride (small quantity of acetonewas added). After washed with 50 ml of saturated brine, the organiclayer was dried over anhydrous sodium sulfate. Solvent was distilled offunder reduced pressure, and the residue obtained was purified by meansof column chromatography (silica gel, methylene chloride:methanol=100:1,quantity of methanol was increased gradually), then recrystallized fromhexane-acetone to obtain 270 mg of aimed product as white crystals.

Melting point 235.5-236.5° C., Mass analysis m/z 353 (M⁺) Elementalanalysis (%) C₁₇H₁₄F₃NO₄ Calcd.(%) C, 57.79; H, 3.99; N, 3.96 Found (%)C, 57.99; H, 3.95; N, 4.01

EXAMPLE 2 4-Methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenylaceticacid

To 2.55 g of publicly known 5-cyanomethyl-2-methoxybenzoic acid wereadded 50 ml of dimethylformamide, 2.57 g of4-trifluoromethylbenzylamine, 2.66 g of diethyl cyanophosphonate and2.00 ml of triethylamine, and the mixture was stirred for 20 minutesunder cooling with ice and for 6 hours at room temperature. The reactionmixture was poured into water and extracted with ethyl acetate. Afterwashed with water, then with saturated brine, the organic layer wasdried over anhydrous sodium sulfate. Solvent was distilled off underreduced pressure, and the residue was crystallized from hexane-diethylether and collected by filtration to obtain 4.44 g of5-cyanomethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide ascolorless crystals. Melting point 124-125° C. Elemental analysis (%)C₁₆H₁₅F₃N₂O₂ Calcd.(%) C, 62.07; H, 4.34; N, 8.04 Found (%) C, 62.03; H,4.27; N, 7.99

To 484 mg of5-cyanomethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added10 ml of ethanol, 0.6 ml of 30% aqueous hydrogen peroxide and 5 ml of0.1 mol/l sodium hydroxide, and the mixture was stirred for 1 hour at50° C. Then, 0.6 ml of 30% aqueous hydrogen peroxide and 5 ml of 0.1mol/l sodium hydroxide were added again and the mixture was stirred for30 minutes at 50° C. The reaction mixture was poured into water andextracted with ethyl acetate. After washed with saturated aqueoussolution of sodium bicarbonate and saturated brine in sequence, theorganic layer was dried over anhydrous sodium sulfate. Solvent wasdistilled off under reduced pressure, and the residue obtained waspurified by means of column chromatography (silica gel, methylenechloride:methanol=100:1 to 50:1) to obtain 318 mg of5-carbamoylmethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide ascolorless crystals.

Melting point 192-193° C. Elemental analysis (%) C₁₈H₁₇F₃N₂O₃ Calcd.(%)C, 59.02; H, 4.68; N, 7.65 Found (%) C, 58.87; H, 4.56; N, 7.63

To 700 mg of5-carbamoylmethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide wereadded 21 ml of ethanol, 7 ml of 1 mol/l aqueous solution of sodiumhydroxide, and the mixture was refluxed for 18 hours. The reactionmixture was poured into water, washed with ethyl acetate, and furtherthe aqueous layer was adjusted to pH value of 1 to 2 with 2 mol/lhydrochloric acid, which was then extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine in sequence anddried again over anhydrous sodium sulfate. Solvent was distilled offunder reduced pressure, and the residue obtained was suspended withdiethyl ether to collect the crystals by filtration. The crystalsobtained were recrystallized from methylene chloride to obtain 435 mg ofaimed product as colorless crystals.

Melting point 167-168° C. Elemental analysis (%) C₁₈H₁₆F₃NO₄ Calcd.(%)C, 58.86; H, 4.39; N, 3.81 Found (%) C, 58.72; H, 4.34; N, 3.86

EXAMPLE 35-[2-Carbamoyl-2-(methylthio)ethyl]-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide

To a suspension of 17.2 g of 2-methoxy-5-nitrobenzoic acid in 35 ml ofmethylene chloride were added 35 ml of oxalyl chloride and one drop ofdimethylformamide, and the mixture was stirred for 1 hour at roomtemperature. Solvent was distilled off under reduced pressure, 150 ml ofdimethylformamide, 15 ml of triethylamine and 16.9 g of4-trifluoromethylbenzylamine were added to the residue, and the mixturewas stirred for 2 hours at room temperature. The reaction mixture waspoured into water and extracted (150 ml×3) with ethyl acetate. Theorganic layer was washed with water and saturated brine in sequence anddried over anhydrous sodium sulfate. Solvent was distilled off underreduced pressure, and the residue obtained was crystallized fromhexane:ethyl acetate=3:1, then the crystals were collected by filtrationto obtain 26.6 g of2-methoxy-5-nitro-N-(4-trifluoromethylbenzyl)benzamide as pale yellowcrystals.

Melting point 108-109° C. Elemental analysis (%) C₁₆H₁₃F₃N₂O₄ Calcd.(%)C, 54.24; H, 3.70; N, 7.91 Found (%) C, 54.27; H, 3.73; N, 7.98

To 26.6 g of 2-methoxy-5-nitro-N-(4-trifluoromethylbenzyl)benzamide wereadded 270 ml of ethyl acetate and 2.6 g of 10% palladium on carbon underan atmosphere of argon, then argon was replaced with hydrogen gas, andthe mixture was stirred for 8 hours at room temperature under anatmosphere of hydrogen gas. Catalyst was filtered through Celite(HyfloSuper-cel) and, after washed the collected material well with ethylacetate, the filtrate was concentrated under reduced pressure. Theresidue obtained was purified by means of column chromatography (silicagel, ethyl acetate) to obtain 24.5 g of5-amino-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as colorlesscrystals.

Melting point 115-117° C. Elemental analysis (%) C₁₆H₁₅F₃N₂O₂ Calcd.(%)C, 59.26; H, 4.66; N, 8.64 Found (%) C, 58.96; H, 4.57; N, 8.68

To a solution of 2.26 g of5-amino-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide in 27 ml ofacetone and 11 ml of methanol were added 5.6 ml of 47% solution ofhydrobromic acid, 540 mg of sodium nitrite and 2 ml of water undercooling with ice, and the mixture was stirred for 10 minutes. To thereaction mixture were added 3.00 g of acrylamide, and, after heated to30° C., 135 mg of cupric oxide were added little by little, and themixture was stirred further for 2 hours at 30° C. Solvent was distilledoff under reduced pressure, and 25% aqueous ammonia was added to theresidue, which was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine in sequence and dried overanhydrous sodium sulfate. Solvent was distilled off under reducedpressure, the residue obtained was crystallized from hexane:ethylacetate=1:1, and then the crystals were collected by filtration toobtain 1.55 g of5-(2-bromo-2-carbamoylethyl)-2-methoxy-N-(4-trifluoromethylbenzyl)benzamideas colorless crystals.

Melting point 192-193° C. Elemental analysis (%) C₁₉H₁₈BrF₃N₂O₃Calcd.(%) C, 49.69; H, 3.95; N, 6.10 Found (%) C, 49.65; H, 3.82; N,6.11

To 1.00 g of5-(2-bromo-2-carbamoylethyl)-2-methoxy-N-(4-trifluoromethylbenzyl)benzamidewere added 60 ml of ethanol and 200 mg of NaSMe, and, after refluxed for3 hours, the mixture was allowed to stand overnight. Solvent wasdistilled off under reduced pressure, and water was added to theresidue, which was extracted with methylene chloride. The organic layerwas washed with saturated brine and dried over anhydrous sodium sulfate.Solvent was distilled off under reduced pressure, and the residueobtained was purified by means of column chromatography (silica gel,hexane:ethyl acetate=1:1) to obtain 865 mg of aimed product as colorlesscrystals.

Melting point 152.5-153.5° C. Elemental analysis (%) C₂₀H₂₁F₃N₂O₃SCalcd.(%) C, 56.33; H, 4.96; N, 6.57 Found (%) C, 56.42; H, 4.97; N,6.55

EXAMPLE 45-[2-Carbamoyl-2-(methylsulfinyl)ethyl]-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide

To 639 mg of5-[2-carbamoyl-2-(methylthio)ethyl]-2-methoxy-N-(4-trifluoromethylbenzyl)benzamidewere added 70 ml of methylene chloride and 368 mg of mCPBA under coolingwith ice, and the mixture was stirred for 3 hours. The reaction mixturewas washed with saturated aqueous solution of sodium bicarbonate andsaturated brine in sequence and dried over anhydrous sodium sulfate.Solvent was distilled off under reduced pressure, and the residueobtained was purified by means of column chromatography (silica gel,methylene chloride:methanol=50:1 to 20:1) to obtain 486 mg of aimedproduct as colorless crystals.

Melting point 170-171° C. Elemental analysis (%) C₂₀H₂₁F₃N₂O₄S Calcd.(%)C, 54.29; H, 4.78; N, 6.33 Found (%) C, 54.11; H, 4.72; N, 6.40

EXAMPLE 55-[2-Carbamoyl-2-(methylsulfonyl)ethyl]-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide

To 274 mg of5-[2-carbamoyl-2-(methylsulfinyl)ethyl]-2-methoxy-N-(4-trifluoromethylbenzyl)benzamidewere added 100 ml of methylene chloride and 155 mg of mCPBA, and themixture was stirred for 3 hours. Saturated aqueous solution of sodiumbicarbonate was added to the reaction mixture, and the insolubles werefiltered off. The organic layer was washed with saturated aqueoussolution of sodium bicarbonate and saturated brine in sequence and driedover anhydrous sodium sulfate. Solvent was distilled off under reducedpressure, and the residue obtained was purified by means of columnchromatography (silica gel, methylene chloride:methanol=50:1 to 20:1) toobtain 201 mg of aimed product as colorless crystals.

Melting point 219-220° C. Elemental analysis (%) C₂₀H₂₁F₃N₂O₅S Calcd.(%)C, 52.40; H, 4.62; N, 6.11 Found (%) C, 52.24; H, 4.52; N, 6.09

EXAMPLE 65-(2-Carbamoyl-2-mercaptoethyl)-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide

To 1.00 g of5-(2-bromo-2-carbamoylethyl)-2-methoxy-N-(4-trifluoromethylbenzyl)benzamidewere added 80 ml of tetrahydrofuran and 368 mg of potassium thioacetateunder an atmosphere of argon, and the mixture was stirred for 6 hours atroom temperature. Solvent was distilled off under reduced pressure, andethyl acetate was added to the residue, which was washed with water andsaturated brine in sequence and dried over anhydrous sodium sulfate.Solvent was distilled off under reduced pressure, and the residueobtained was crystallized from hexane-ethyl acetate, then the crystalswere collected by filtration to obtain 904 mg of5-(2-acetylthio-2-carbamoylethyl)-2-methoxy-N-(4-trifluoromethylbenzyl)benzamideas light brown crystals.

Melting point 159-161° C. Elemental analysis (%) C₂₁H₂₁F₃N₂O₄S Calcd.(%)C, 55.50; H, 4.66; N, 6.16 Found (%) C, 55.32; H, 4.58; N, 6.18

To 300 mg of5-(2-acetylthio-2-carbamoylethyl)-2-methoxy-N-)4-trifluoromethylbenzyl)benzamidewere added 30 ml of saturated ammoniacal methanol under an atmosphere ofargon, and the mixture was stirred for 3 hours at room temperature.Solvent was distilled off under reduced pressure, and the residueobtained was recrystallized from hexane-ethyl acetate to obtain 195 mgof aimed product as colorless crystals.

Melting point 159-161° C. Elemental analysis (%) C₁₉H₁₉F₃N₂O₃S Calcd.(%)C, 55.33; H, 4.64; N, 6.79 Found (%) C, 55.08; H, 4.63; N, 6.82

EXAMPLE 73-[4-Methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylthio)propionicacid

To a solution of 17.3 g of5-amino-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide in 170 ml ofacetone and 85 ml of methanol were added 43 ml of 47% solution ofhydrobromic acid and 17 ml of aqueous solution of 4.15 g of sodiumnitrite under cooling with ice-salt, and the mixture was stirred for 10minutes. To the reaction mixture were added 26 ml of methyl acrylate,and, after heated to 30° C., 1.04 g of cupric oxide were added little bylittle, and the mixture was stirred further for 1 hour at 40 to 50° C.Solvent was distilled off under reduced pressure, and 25% aqueousammonia was added to the residue, which was extracted with ethylacetate. The organic layer was washed with water and saturated brine insequence and dried over anhydrous sodium sulfate. Solvent was distilledoff under reduced pressure, and the residue obtained was crystallizedfrom hexane-ethyl acetate, then the crystals were collected byfiltration to obtain 10.3 g of methyl2-bromo-3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-propionateas light brown crystals.

Melting point 110-111° C. Elemental analysis (%) C₂₀H₁₉BrF₃NO₄ Calcd.(%)C, 50.65; H, 4.04; N, 2.95 Found (%) C, 50.74; H, 3.86; N, 3.05

To 2.00 g of methyl2-bromo-3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]propionatewere added 100ml of absolute methanol and 380 mg of NaSMe, and themixture was refluxed for 6 hours. Solvent was distilled off underreduced pressure, and water was added to the residue, which wasextracted with methylene chloride. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. Solvent wasdistilled off under reduced pressure, and the residue obtained waspurified by means of column chromatography (silica gel, hexane:ethylacetate=1:1) to obtain 1.23 g of methyl3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylthio)propionateas colorless crystals.

Melting point 127-128° C. Elemental analysis (%) C₂₁H₂₂F₃NO₄S Calcd.(%)C, 57.13; H, 5.02; N, 3.17 Found (%) C, 57.01; H, 4.91; N, 3.19

To 300 mg of methyl3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]-carbamoylphenyl]-2-(methylthio)propionatewere added 7 ml of methanol and 3 ml of aqueous solution of 33 mg oflithium hydroxide, and the mixture was stirred for 1 hour at roomtemperature, then refluxed further for 5 hours. Solvent was distilledoff under reduced pressure, and water was added to the residue, whichwas washed with diethyl ether. The aqueous layer was adjusted to pHvalue of 1 to 2 with 2mol/l hydrochloric acid and extracted with diethylether. After washed with water, the organic layer was dried overanhydrous sodium sulfate. Solvent was distilled off under reducedpressure, and the residue obtained was recrystallized fromhexane-acetone to obtain 239 mg of aimed product as colorless crystals.

Melting point 170-171° C. Elemental analysis (%) C₂₀H₂₀FNO₄S Calcd.(%)C, 56.20; H, 4.72; N, 3.28 Found (%) C, 56.14; H, 4.56; N, 3.20

EXAMPLE 83-[4-Methoxy-3-[N-(4-trifluoromethylbenzyl)]-carbamoylphenyl]-2-(methylsulfinyl)propionicacid (high-polarity form and low-polarity form)

To 1.00 g of3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]-carbamoylphenyl]-2-(methylthio)propionicacid were added 20 ml of acetone, 600 mg of benzyl bromide and 490 mg ofpotassium carbonate, and the mixture was refluxed for 1 hour. Thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with water and saturated brine in sequenceand dried over anhydrous sodium sulfate. Solvent was distilled off underreduced pressure, and the residue obtained was purified by means ofcolumn chromatography (silica gel, hexane:diethyl ether=5:1). Aftercrystallized from hexane:diethyl ether, the crystals were collected byfiltration to obtain 1.13 g of benzyl3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylthio)propionateas colorless crystals.

Melting point 77-79° C. Elemental analysis (%) C₂₇H₂₆F₃NO₄S Calcd.(%) C,62.66; H, 5.06; N, 2.71 Found (%) C, 62.72; H, 5.06; N, 2.76

To a solution of 1.00 g of benzyl3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylthio)-propionatein 20 ml of methylene chloride were added 429 mg of mCPBA under coolingwith ice, and the mixture was stirred for 30 minutes. The reactionmixture was washed with saturated aqueous solution of sodium bicarbonateand saturated brine in sequence and dried over anhydrous sodium sulfate.Solvent was distilled off under reduced pressure, and the residueobtained was purified by means of column chromatography (silica gel,methylene chloride:methanol=100:1) to obtain 915 mg of diastereomermixture of benzyl3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfinyl)-propionateas colorless oily product. This diastereomer mixture was separated usinghigh performance liquid chromatography (column: Inertsil ODS-2, columntemperature: 25° C., mobile phase: acetonitrile:diluted phosphoric acid(1→1000)=1:1, 7.5 ml/min, measurement wavelength:240 nm), and respectiveeluate was extracted with methylene chloride and dried over anhydroussodium sulfate. Solvent was distilled off under reduced pressure, andrespective residue obtained was purified by means of columnchromatography (silica gel, methylene chloride: methanol=100:1) toobtain 383 mg of high-polarity benzyl ester form and 514 mg oflow-polarity benzyl ester form.

High-polarity benzyl ester form: 400 MHz ¹-NMR(CDCl₃) δ: 2.55 (1H, s,SOMe), 3.32(2H, d, J=8 Hz, CH₂ CHS), 3.79(1H, t, J=8 Hz, CH₂CHS),3.93(3H, s, OMe), 4.73(2H, d, J=6 Hz, CH₂N), 5.15(1H, d, J=12 Hz,OCH₂Ar), 5.22(1H, d, J=12 Hz, OCH₂Ar), 6.87(1H, d, J=8.4 Hz, ArH),7.26-7.34(6H, m, ArH), 7.47(2H, d, J=8 Hz, ArH), 7.60(2H, d, J=8 Hz,ArH), 8.12(1H, d, J=2.4 Hz, ArH), 8.27(1H, t, J=6 Hz, CONH)High-resolution mass analysis C₂₇H₂₇F₃NO₅(M+1): Calcd.:534.1562, Found534.1592

Low-polarity benzyl ester form: 400 MHz ¹H-NMR(CDCl₃) δ: 2.60 (1H, s,SOMe), 3.26(1H, dd, J=10.4, 14 Hz, CH₂ CHS), 3.35(2H, dd, J=4.4, 14 Hz,CH₂ CHS), 3.79(1H, dd, J=4.4, 10.4 Hz, CH₂CHS), 3.93(3H, s, OMe), 4.74(2H, d, J=6 Hz, CH₂N), 5.13(2H, s, OCH₂Ar), 6.86(1H, d, J=8.8 Hz, ArH),7.22-7.32(6H, m, ArH), 7.47(2H, d, J=8 Hz, ArH), 7.60(2H, d, J=8 Hz,ArH), 8.11(1H, d, J=3.2 Hz, ArH), 8.26(1H, t, J=6 Hz, CONH)High-resolution mass analysis C₂₇H₂₇F₃NO₅S(M+1): Calcd.: 534.1562, Found534.1562

To 370 mg of benzyl 3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]-carbamoylphenyl]-2-(methylsulfinyl)-propionate (high-polarity benzylester form) obtained by separation were added 20 ml of ethanol and 100mg of 7.5% palladium on carbon (sulfur-tolerant) under an atmosphere ofargon gas, then argon gas was replaced with hydrogen gas, and themixture was stirred for 2 hours at room temperature under an atmosphereof hydrogen gas. Further, additions of 100 mg of 7.5% palladium oncarbon (sulfur-tolerant) and stirrings of the mixture for 2 hours andfor 1 hour were repeated, respectively, under an atmosphere of hydrogengas to complete the reaction. Catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The residueobtained was purified by means of column chromatography (silica gel,methylene chloride:ethyl acetate=50:1 to methylenechloride:methanol:acetic acid=50:1:1), then recrystallized from diethylether-acetone to obtain 176 mg of3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]-carbamoylphenyl]-2-(methylsulfinyl)propionicacid (high-polarity form) as colorless crystals.

Melting point 135-137° C. Test of purity by means of high performanceliquid chromatography: 99% de (measuring conditions; column InertsilODS-3, φ4.6×250 mm, measurement wavelength 240 nm, flow rate 1.0 ml/min,mobile phase acetonitrile:diluted aqueous phosphoric acid(1→1000)=45:55, column temperature 30° C.) Elemental analysis (%)C₂₀H₂₀F₃NO₅S Calcd.(%) C, 54.17; H, 4.55; N, 3.16 Found (%) C, 53.94; H,4.51; N, 3.13 400 MHz ¹H-NMR(d₆-DMSO) δ: 2.66 (1H, s, SOMe), 3.05(1H,dd, J=5.5, 14 Hz, CH₂ CHS), 3.10(1H, dd, J=10, 14 Hz, CH₂ CHS),3.85-3.93(4H, m, CH₂CHS, OMe), 4.57(2H, d, J=6 Hz, CH₂N), 7.10(1H, d,J=8.5 Hz, ArH), 7.37(1H, dd, J=2.4, 8.5 Hz, ArH), 7.54(2H, d, J=8 Hz,ArH), 7.66(1H, d, J=2.4 Hz, ArH), 7.70 (2H, d, J=8 Hz, ArH), 8.82(1H, t,J=6 Hz, CONH), 13.10(1H, br s, COOH)

Similarly, 480 mg of benzyl3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfinyl)propionate(low-polarity benzyl ester form) obtained by separation weredebenzylated reducibly to obtain 270 mg of3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]-carbamoylphenyl]-2-(methylsulfinyl)propionicacid (low-polarity form) as colorless crystals.

Melting point 127-128° C. High-resolution mass analysis C₂₀,H₂₁F₃NO₅S(M+1): Calcd.: 444.1093, Found 444.1090 400 MHz ¹H-NMR(d₆-DMSO)δ: 2.68(1H, s, SOMe), 3.02(1H, dd, J=10, 13.8 Hz, CH₂ CHS), 3.11(1H, dd,J=4, 13.8 Hz, CH₂ CHS), 3.86-3.91(4H, m, CH₂CHS, OMe), 4.57(2H, d, J=6Hz, CH₂N), 7.11(1H, d, J=8.8 Hz, ArH), 7.38(1H, dd, J=2.4, 8.8 Hz, ArH),7.54(2H, d, J=8 Hz, ArH), 7.66(1H, d, J=2.4 Hz, ArH), 7.70 (2H, d, J=8Hz, ArH), 8.82(1H, t, J=6 Hz, CONH), 13.22(1H, br s, COOH) Test ofpurity by means of high performance liquid chromatography: 98%de(measuring conditions; column Inertsil ODS-3, φ4.6×250mm, measurementwavelength 240 nm, flow rate 1.0 ml/min, mobile phaseacetonitrile:diluted aqueous phosphoric acid (1→1000)=45:55, columntemperature 30° C.)

EXAMPLE 93-[4-Methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfonyl)propionicacid

To a solution of 1.50 g of methyl3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylthio)propionatein 30 ml of methylene chloride were added 800 mg of mCPBA under coolingwith ice, and the mixture was stirred for 30 minutes. The reactionmixture was washed with saturated aqueous solution of sodium bicarbonateand saturated brine in sequence and dried over anhydrous sodium sulfate.Solvent was distilled off under reduced pressure, and the residueobtained was purified by means of column chromatography (silica gel,methylene chloride:methanol=100:1 to 50:1) to obtain 1.22 g of methyl3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfinyl)-propionateas colorless crystals. To a solution of 1.02 g of methyl3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]-carbamoylphenyl]-2-(methylsulfinyl)propionateobtained in 20 ml of methylene chloride were added 550 mg of mCPBA undercooling with ice, and the mixture was stirred for 7 hours at roomtemperature. The reaction mixture was washed with saturated aqueoussolution of sodium bicarbonate and saturated brine in sequence and driedover anhydrous sodium sulfate. Solvent was distilled off under reducedpressure, and the crystals obtained were recrystallized fromhexane-ethyl acetate to obtain 750 mg of methyl3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfonyl)propionateas colorless crystals. Melting point 144-145° C.

Elemental analysis (%) C₂₁H₂₂F₃NO₆S Calcd.(%) C, 53.27; H, 4.68; N, 2.96Found (%) C, 53.12; H, 4.48; N, 3.00

Into 6 ml of methanol were dissolved 300 mg of methyl3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfonyl)propionate,0.7 ml of 1 mol/l aqueous solution of sodium hydroxide were added, andthe mixture was stirred for 1 hour at 50° C. The reaction mixture waspoured into water and washed with diethyl ether. The aqueous layer wasadjusted to pH value of 1 to 2 with 2 mol/l aqueous solution ofhydrochloric acid, which was extracted with methylene chloride. Theorganic layer was washed with water and saturated brine in sequence anddried over anhydrous sodium sulfate. Solvent was distilled off underreduced pressure, and the crystals obtained were recrystallized fromdiethyl ether-ethyl acetate to obtain 218 mg of aimed product ascolorless crystals.

Melting point 158-159° C. Elemental analysis (%) C₂₀H₂₀F₃NO₆S Calcd.(%)C, 52.29; H, 4.39; N, 3.05 Found (%) C, 52.11; H, 4.20; N, 3.05

Test Example 1

Test of transcriptional activation on peroxisome proliferator-activatedreceptors α and γ

To CHO cells cultured in a Ham's F-12 medium with 10% fetal calf serum,receptor plasmid that expresses fused protein of DNA-binding domain ofGAL4 being transcription factor of yeast with ligand binding domain ofhuman type PPARs α and γ (Biochemistry, 1993, 32, 5598), fireflyluciferase reporter plasmid (Promega Corp.) that is activated by GAL4and sea shiitake mushroom luciferase plasmid (Promega Corp.) forinternal standard were cotransfected with lipofectamine. Thereafter,testing compound dissolved into dimethyl sulfoxide (DMSO) (finalconcentration of DMSO 0.1%) and control drug were adjusted with Ham'sF-12 medium containing 10% defatted fetal calf serum to culture. After24 hours, the luciferase activity was measured. Results are shown intable.

TABLE Transcriptional activity PPARα Example EC₅₀ (μmol/l) 3 2.1 7 1.2(8S)-HETE 1.3

From these results, it was shown that the inventive compounds had potenttranscriptional activity on human peroxisome proliferator-activatedreceptor.

Utilizability in the Industry

From the results as described above, it has become clear that theinventive novel o-anisamide derivatives have excellent human PPARtranscriptional activity. These compounds are useful for the preventionand therapy of metabolic diseases such as hyperlipidemia and diabetes,in which PPAR precipitates, as agonistic drugs on human PPAR.

What is claimed is:
 1. An o-anisamide compound represented by a generalformula (1)

wherein R denotes a carboxyl group, carboxymethyl group or CH₂CHXCOY,wherein X denotes a mercapto group or S(O)nMe, n=0, 1 or 2, and Ydenotes an amino group or hydroxyl group; or a medicinally acceptablesalt or hydrate thereof.
 2. The compound of claim 1, being4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylbenzoic acid.
 3. Thecompound of claim 1, being4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenylacetic acid. 4.The compound of claim 1, being5-[2-carbamoyl-2-(methylthio)ethyl]-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide.5. The compound of claim 1, being5-[2-carbamoyl-2-(methylsulfinyl)ethyl]-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide.6. The compound of claim 1, being5-[2-carbamoyl-2-(methylsulfonyl)ethyl]-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide.7. The compound of claim 1, being5-[2-carbamoyl-2-(mercapto)ethyl]-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide.8. The compound of claim 1, being3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylthio)propionicacid.
 9. The compound of claim 1, being3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfinyl)propionicacid.
 10. The compound of claim 1, being3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfonyl)propionicacid.
 11. An agonistic drug on human peroxisome proliferator-activatedreceptor (PPAR) comprising at least one o-anisamide compound representedby a general formula (1)

wherein R denotes a carboxyl group, carboxymethyl group or CH₂CHXCOY,wherein X denotes a mercapto group or S(O)nMe, n=0, 1 or 2, and Ydenotes an amino group or hydroxyl group; or a medicinally acceptablesalt or hydrate thereof, as effective ingredients.
 12. A method ofpreventing or treating a metabolic disease in which peroxisomeproliferator-activated receptor participates, in a subject, comprisingadministering the agonistic drug of claim 11 to said subject whereinsaid metabolic disease is at least one selected from the groupconsisting of hyperlipidemia and diabetes.
 13. The method of claim 12,wherein the method is preventing and the disease is hyperlipidemia. 14.The method of claim 12, wherein the method is preventing and the diseaseis diabetes.
 15. The method of claim 12, wherein the method is treatingand the disease is hyperlipidemia.
 16. The method of claim 12, whereinthe method is treating and the disease is diabetes.